Clinical data support the concept that both normal stem cells and leukemia stem cells exhibit multiple drug resistance. However, it is unclear how mechanisms for drug resistance might interrelate with stem cell physiology. Our preliminary studies have explored the physiology of multiple drug resistance using the L1210cpa cell line. Collectively, our data suggest that drug resistant cells are critically sensitive to their intracellular concentration of glucose. L1210cpa cells import glucose efficiently. However, gene expression analyses also suggest that their supply of glucose is dependent upon gluconeogenesis and the availability of intermediates for the TCA cycle. We propose that these pathways relate to the cell's capacity to respond to oxidative stress, and that they represent a fundamental hallmark for drug resistance. We further propose that these pathways are critical determinants for the maintenance of stem cell viability or function. The ultimate goal for these studies is to more effectively kill primary leukemia stem cells. Our preliminary studies demonstrate that proliferation by L1210cpa cells is strongly inhibited by 2-deoxy-D-glucose (2-DG), cyclosporin A (CsA) and rapamycin. These agents represent clear candidates that might be used to develop adjunct therapies. We propose that these agents might disrupt a cell's capacity to respond to oxidative stress. Alternatively, 2-DG, CsA and rapamycin might perturb essential stem cell functions for self-renewal or regeneration. These hypotheses will be tested using normal stem cells isolated from human umbilical cord blood and CD34+ AML stem cells isolated from bone marrow samples taken from human patients that have failed prior therapies. Finally, with the intent of identifying other pathways that might be developed as therapeutic targets, our studies will continue to interrogate how glucose metabolism is regulated within the drug resistant L1210cpa cells. PUBLIC HEALTH RELEVANCE: Multiple drug resistance is a significant clinical problem in the treatment of leukemia. When present, the surviving tumor cells then repopulate the tumor to fulfill one fundamental property for a stem cell: regeneration. Therefore, strong in vivo data support the concept that leukemia stem cells exhibit multiple drug resistance. However, precisely how drug resistance and stem cell physiology interrelate still remains largely unresolved. These studies explore that relationship to help lay the groundwork for therapies that specifically target multiple drug resistance and leukemia stem cells.